7alpha-methyl-3, 5-androstadiene-3, 17-diols and pharmaceutically active compositions thereof



United States Patent 0 ABSTRACT OF THE DISCLOSURE This invention relatesto novel steroids, more particularly to the 3-enol acylates, 3,l7-dienoldiacylates and 3- enol ethers of certain 7a-methyl-4-androstenes,2u,7a-dimethyl-4-androstenes and their 19-nor-counterparts of theformula 3,383,282 Patented May 14, 1968 wherein R and R are selectedfrom the group consisting of hydrogen and methyl; Z is selected from thegroup consisting of lower alkyl of from one to twelve carbon atoms,inclusive, and the lower acyl radical of a hydrocarbon carboxylic acidcontaining from one to twelve carbon atoms, inclusive; M is selectedfrom the group consisting of 5 oz oz o O--CECA) c m and wherein A isselected from the group consisting of hydrogen, loWer-alkyl of from oneto twelve carbon atoms, inclusive, chlorine, bromine andtrifiuoromethyl, R is selected from the group consisting of hydrogen,lower alkyl of from one to twelve carbon atoms, inclusive, and Z isselected from the group consisting of hydrogen and the lower acylradical of a hydrocarbon carboxylic acid containing from one to twelvecarbon atoms, inclusive.

The compounds of the present invention and the processes for theirproduction are illustratively represented by the following sequence offormulae:

ciig wherein R R Z, C and A have the same meaning as above; R has thesame meaning as R R is a lower alkyl radical containing from one totwelve carbon atoms, inelusive.

The S-enol acylates (of Formulae Ia, 1114:, Wu and Va) and 3-enol ethers(of Formulae Ia, IIa, IIIa, Na and Va) of the invention are preparedfrom the known 7amethyl-4-androstene starting materials of Formula I ofthe flow-sheet, above, which are synthesized in the manner of Campbelland Babcock (J. Amer. Chem. Soc. 81, 4069). The corresponding2a,7a-dimethyl compounds (I) are produced in accordance with theprocedures of US. Patent 2,923,720.

Oxidation of the compounds of Formula I, e.g.,7amethyl-l9-nor-l7,B-hydroxy-4-androstene-3-one (I) andZaJa-dimethyI-I7B-hydroxy-4-androstene-3-one (I), with oxidizing agentssuch as chromic acid, sodium dichromate, potassium dichromate, and thelike, using procedures known in the art, yields7a-methyl-l9-nor-4-androstene- 17-one (II) and211,7a-dimethyl-4-androstene-3,l7-dione (I).

The 7u-methyl (and 2a,7a-dimethyl)-3,l7-diketo-4- androstenes andl9-nor-androstenes of Formula II, prior to the formation of theircorresponding l7a-alkynyl and haloalkynyl derivatives (III) and 17 alkylderivatives (V), must first be converted to the correspondingB-enamines, 3-ketals, or 3-enol ethers in order to protect the 3-ketofunction from reduction. The 3-enamine formation can be accomplished inthe manner described in U.S. Patent 2,781,343, namely, by reaction witha secondary cyclic alkyleneamine containing from to 7 ring atoms,inclusive, such as pyrrolidine, piperidine, morpholine, and C- alkylsubstituted pyrrolidines, piperidines, and morpholines such as2,4-dimethylpyrrolidine, 3-propylpiperidine, Z-methylpyrrolidine, 3,4dimethyl-pyrrolidine, 3-ethylpyrrolidine, 3-isopropylpyrrolidine,3,3-dimethylpyrrol'- idine, Z-methylmorpholine, 3methylmorpholine, andthe like. Pyrrolidine is the preferred amine for use in the abovereaction.

Advantageously, the 3-enamine is prepared by mixing the 7a-methyl (and2a,7a-din1ethyl) 4 androstene-3, 17-diones (II) and the secondary cyclicalkyleneamine together in the presence of a suitable solvent, forexample, a lower alkanol such as methanol, ethanol, and the like. Thedesired 3-enamine generally separates from the reaction mixture and isisolated and dried for a short period before being used without furtherpurification in the next stage of the synthesis.

The 3-enamines of 7a-methyl (and 2a,7a-dimethyl)-4-androstene-3,17-diones (II) so obtained are then reacted with anorgano-alkali metal derivative, for example, the sodium or potassiumderivative of the appropriate alkyne. The reaction is carried outpreferably in the presence of an anhydrous inert solvent such asdimethylformamide, dimethylsulfoxide, and the like. The B-enamines ofthe 7CL-1I16Ihy1 (and 2a,7a-dimethyl) 17a alkynyltestosterones (III) soobtained are not generally isolated from the reaction mixture but arehydrolyzed in situ to the free 7a-methyl (and 2a,7a-dimethyl) aalkynyltestosterones (III) by treatment with an aqueous solution of abase such as sodium hydroxide, potassium hydroxide, and the like, afterfirst decomposing the reaction mixture with water, ammonium chloride,and the like.

The 70c methyl (and 2a,7a-dimethyl) 17cc alkynyltestosterones (IV) soobtained can be purified, if desired, by procedures known in the artsuch as by recrystallization, chromatography, and the like.

The 7:! methyl (and 2a,7 x-dimethyl)-17a-alkynyltestosterones (III) canalso be prepared by reacting the 3- enamines of the 70: methyl (and204,7 dimethyl)-4- androstene-3,17-diones (II), prepared as describedabove, with the appropriate alkynyl magnesium halide. The reaction ispreferably carried out in the presence of a solvent such as diethylether, tetrahydrofuran, and the like. Preferably, the Grignard reagentis employed in an excess of the order of 10 moles per mole of the 3-enamine. The 3-enarnines of 7a-methy1 (and 2a,7a-dimethyl)l7a-alknyltestosterone (III) so obtained are generally not isolated fromthe reaction mixture but are hydrolyzed in situ to the free 7a-methyl(and 20c,7oc-(limethyl) 17a alkynyltestosterones (III) by the methoddescribed above.

In converting the 7a-methyl (and 2a,7a-dimethyl)-3, 17diketo-4-androstenes (II) to their corresponding 17aalkynyl andhaloalkynyl derivatives (III), 3-keto protecting groups in addition tothe S-enamines described above, such as 3-ketals and 3-enol ethers, canbe employed. Treatment of a 3-ketal or 3-enol ether of a compound ofFormula II with an alkali metal derivative, e.g., an appropriate alkyneor haloalkyne, yields the corresponding 3-ketone of Formula III. Methodsfor the preparation of 3-ketals and 3-enol ethers of a variety of 3-ketocompounds of the androstane series, and their subsequent alkynylation orhaloalkynylation, are described in detail in J. Chem. Soc., 4995 (1962).

The alkynyl compounds of Formula III can be readily reduced at theNot-position (e.g., with hydrogen in the presence of a palladiumcatalyst) to give selectively the corresponding side-chain saturatedcompound (IV). For example by employing the foregoing procedure,70cmethyl-l9-nor-17/3-hydroxy 170a ethynyl 4 androsten- 3-one (III) isconverted to lax-methyl l9 nor 17B- hydroxy 17oz ethyl-4-androsten-3-one(IV).

The 17-ketones represented by Formula II can be converted to thecorresponding 17B-hydroxy-17a-alkyl derivatives (V) by treatment with anappropriate alkylating agent such as an appropriate Grignard reagent oralkyl lithium compound. Before converting the compounds of Formula II tothe 17a-alkyl compounds (V) by the above procedure, however, it isnecessary to first attach a protecting group at the 3-position, e.g., anenamine; this can be carried out in the manner described hereinbeforefor preparing the 17a-alkynyl compounds (III) from the corresponding17-ketones (II). The 17a-alkylated-3- enamine produced by the reactionof an appropriate alkylating agent (e.g., a Grignard reagent or alkyllithium) with a S-enamine of a compound of Formula II is generally notisolated from the reaction mixture, but is hydrolyzed in situ to thecorresponding 7a-methyl (or 2a,7a-dimethyl) 17a alkyl derivative (V) bytreatment with an aqueous solution of a base such as sodium hydroxide,potassium hydroxide, etc., after first decomposing the reaction mixturewith water, ammonium chloride, and the like. By following the foregoingprocedure, Za h-dimethyl 4 androstene 3,17 dione 3-pyrrolidinyl enamine(II) is converted to 2a,7ot,17a trimethyl 17B hydroxy-4-androsten-3-one(V).

The A -3-ketones represented by Formulae I, II, III, IV, and V of theflow-sheet, above, are readily converted to the corresponding3,17-dienol diacylates of Formulae Ia, IIa, IIIa, Na and Va,respectively. This conversion is a well known reaction. Treating the A-3-ketone with an anhydride, a chloride, or bromide of an organiccarboxylic acid, preferably a hydrocarbon carboxylic acid containingfrom one to twelve carbon atoms, inclusive, in the presence of an acidcatalyst such as paratoluenesulfonic acid, perchloric acid, sulfuricacid, and the like, or with an isopropenyl acylate wherein the acylgroup is that of a hydrocarbon carboxylic acid is defined above, yieldsthe corresponding 3-acyloxy 3,5 diene and the 3,17-diacyloxy 3,5 1-6triene. The reaction is usually carried out at the refluxing temperatureof the reaction mixture, e.g., between about 30 C. to about 150 C. Anexcess of acylating agent, two to twenty moles per mole of A -3-ketone,is usually employed. Aromatic hydrocarbons, e.g., benzene or toluene,methylene chloride, chloroform, and carbon tetrachloride are convenientsolvents for the acylation reaction. The 3-monoacylate and3,17-diacy1ate products can be isolated by removing the solvents, byevaporation under diminished pressure or atmospheric pressure(preferably, in an atmosphere of nitrogen), and washing the productswith water to remove the catalyst. Alternatively, excess acylating agentcan be destroyed by addition of water or an alkanol and the productsthen isolated by extraction or by precipitation with a large quantity ofwater.

The 3,5-androstadiene 3-monoacylates and 19-nor derivatives thereofembraced by Formulae Ia, IIa, IIIa, Na and Va of the flow-sheet, above,can also be conveniently prepared in accordance with the followingreaction:

wherein Ac is the acyl radical of a hydrocarbon carboxylicacidcontaining from one to twelve carbon atoms, inclusive, R R A, Z and Mhave the same meaning as on columns l, 2 and 3, 4, except that in thesecond value indicated thereat for M, R is other than hydrogen. The6-dehydrotestosterone starting materials (prepared as in U.S. Patent2,739,974 or by the reaction of testosterones with chloranil) arereacted with an excess e.g., 1.1 to 10 moles of a Grignard reagent,e.g., methyl magnesium iodide, methyl magnesium bromide and the like, inthe presence of cuprous chloride or an equivalent catalyst, cuprouschloride being preferred. An anhydride of a hydrocarbon carboxylic acidin a solvent (preferably tetrahydrofuran) is added and the reactionmixture agitated at or near room temperature, preferably for severalhours. Various inert solvents can be employed in carrying out thereaction, e.g., benzene, toluene, ethylene glycol dimethyl ether andtetrahydrofuran, the lattermost being preferred. The 3,5-andros-tadieneand norandrostadiene 3-monoacylate products are isolated by decomposingthe excess anhydride, removing the solvents and catalysts by standardprocedures well known in the steroid art. The whole operation is carriedout with exclusion of oxygen, by treating the reactants in an atmosphereof nitrogen and by purging (-with nitrogen) the solvents employed inextraction of the products as well as the resulting extracts. The crude3-monoacylates are purified by chromatography, recrystallization orother commonly used known methods.

The A -3-keto compounds embraced by Formulae I, II, III, IV and V areconverted to their corresponding 3-enol ethers represented by FormulaIa, Ila, IIIa, Na and Va, respectively, by known methods, e.g., byreaction with a trialkyl orthoformate in the presence of a catalyst suchas paratoluenesulfonic acid, hydrochloric acid, and the like, inaccordance with known procedures, e.g., those described in Ber., 71,1766.

The compounds of Formulae Ia through Va of the present invention haveanabolic and androgenic activity of improved therapeutic ratio of theformer versus the latter. They also exhibit improved solubilityproperties in oil vehicles, e.g., sesame oil, cottonseed oil and thelike suitable for intra muscular injection, thus permitting moreeffective doses of steroid to be administered in a practical volume ofoil and prolonging the duration of biological effect. They also possesserythropoietic, anti-fertility, antiandrogenic and anti-estrogenicactivities. They also have the ability to reduce the level ofcholesterol in the blood and disease blood clotlysis time andconsequently are of value in the treatment or prevention ofatherosclerosis and thromboembolic disorders. The foregoing propertiesmake the new compounds useful in medical and veterinary practice.

The compounds of the invention can be prepared and administered tomammals, birds, humans, and animals, in a wide variety of oral orparenteral dosage forms, singly or in admixture with other coactingcompounds. They can be administered with a pharmaceutical carrier whichcan be a solid material or a liquid in which the compound is dissolved,dispersed or suspended. The solid compositions can take the form oftablets, powders, capsules, pills, or the like, preferably in unitdosage forms for simple administration or precise dosages. The liquidcompositions can take the form of solutions, emulsions, suspensions,syrups, or elixirs.

Example 1.2a,7a-dimethyl-1 7B-hydr0xy-4-andr0stene- 3-0ne(2a,7a-dimethyltestosterone) (I) A solution of 9.96 g. (0.331 mole) of7u-methyl-17B- hydroxy-4-androstene-3-one (7a-methyltestosterone) (I)(prepared in the manner disclosed in J. Amer. Chem. Soc., 81, 4069) in150 ml. of 5-butyl alcohol was treated with stirring at about 60 C. with10 ml. of ethyl oxalate followed by 13 ml. of 25 percent sodiummethoxide solution. Heating was stopped and stirring continued for about20 minutes, while the temperature of the reaction mixture was allowed todecline without external cooling. After the addition of about ml. ofanhydrous ether and a further period of about 20 minutes of stirring,the yellow glyoxalate was collected by filtration, washed with ether anddried at about 70 C. in vacuo. The crude glyoxalate weighing 9.17 g wasmixed with 30 g. of potassium carbonate, 30 ml. of methyl iodide and 250ml. of acetone; the mixture was stirred while heating under gentlereflux for a period of about 24 hours. The reflux condenser was removedand the reaction flask arranged for distillation. After between about 75and 100 ml. had distilled, the reaction mixture was filtered and thefiltrate evaporated to dryness to give g. of solid. This material wasdissolved in 125 ml. of methanol, purged with nitrogen and treated with10 ml. of similarly purged 25 percent sodium methoxide solution. Afterabout 2 hours at room temperature, 250 ml. of saturated salt solutionwas added, the mixture extracted with methylene chloride, dried andevaporated to an amber gum. This crude product was purified bychromatography on 350 g. of Florisil (synthetic magnesium silicate).Thirty-five fractions of 550 ml. volume were collected using a gradientfrom 100 percent Skellysolve B (hexane hydrocarbons) to 10 percentSkellysolve B (hexane hydrocarbons) to 10 percent acetone-90 percentSkellysolve B. Fractions 18 to 28 contained 2.68 g. of crystals whichafter two recrystallizations from a mixture of acetone and Skellysolve Bgave pure 2u,7a-dimethyl-17fi-hydroxy-4-androstene-3-one (1), melting at170 to 180 C.;

Milk. 2 u; 1 3133? and 1,075 cm.-

Analysis.-Calcd. for C I-1 0 C, 79.70; H, 10.19. Found: C, 79.59; H,10.49.

Following the procedure of Example 1, but Substituting for the startingsteroid 7tx-methyl-17f3-hydroXy-4-androsten-3-one (I), the followingrepresentative starting material 7amethyl-19-nor-17,8-hydroxy-4-androstene-3-one (I), yields2a,7a-dimethyl-l9-nor-17fl-hydroXy-4-androsten-3-one (1).

Example 2.2a,7a,1 7a-Irimethyl-I 7fi-Izydr0xy-4-andr0- sten-3-0ne(2a,7a,1 7a-trimethyltestosterone) (I) To a solution of 50 g. of7a,Not-dimethyl-17,8-hydroxy- 4-androsten 3 one (70:,170:dimethytestosterone) (I) (prepared as in J. Amer. Chem. Soc. 81, 4069)in 750 ml. of t-butyl alcohol, warmed to 55 C. in a nitrogen atmosphere.50 ml. of ethyl oxalate and 65 ml. of 25 ercent sodium methoxidesolution was added with stirring. Stirring was continued for aboutminutes after which 750 ml. of ether was added. The mixture was filteredand the solid of yellow glyoxalate dried under nitrogen in a vacuum ovento give 46 g. of crude material. A mixture of the crude glyoxalate, 150g. of potassium carbonate, 150 ml. of methyl iodide and 1250 ml. ofacetone was stirred and heated under reflux for about 24 hours.Approximately 500 ml. of liquid was distilled off and the remainingmixture filtered. The filter cake was washed with acetone and thecombined mixture filtered. The cake was washed with additional acetoneand the combined filtrate evaporated at reduced pressure to an amber gumwhich was dissolved in 625 ml. of methanol purged with nitrogen andtreated with 50 ml. of percent sodium methoxide solution. After about 2hours, 1400 ml. of saturated sodium chloride solution was added, and themixture extracted with methylene chloride. The extract was dried and thesolvent evaporated. The crude gummy product was purified viachromatography on a 2.5 kg. column of Florisil. A mixture composed of 6percent of acetone and the remainder. Skellysolve B eluted 13.34 g. ofcrystals, which on recrystallization from acetone-Skellysolve B yielded11.53 g. of the desired product (I) melting at 158 to 159 C. A portionof this material was recrystallized from the same solvent pair toprovide an analytical sample of pure 10L,70t,l7ottrimethyl-17/3-hydroxy-4-androstene-3-one (I) melting at 158 to 159 C.;

M12, 2 12 In 6=15,50U; villi? 3435, 1.13155, 1622, 1220, 1100, 1075 our.(index Il0,881)

Depression of the melting point of the product (I wherein R =CH occurredon mixture with the starting material (I wherein R =H).

Analysis.Calcd. for C H O C, 79.95; H, 10.37. Found: C, 79.60; H, 10.48.

Following the procedure of Example 2, but substituting for the startingsteroid 7a,Hot-dimethyl-17fl-hydr0xy-4- androsten-3-one (I), thefollowing representative starting materials, 7a,17a dimethyl l9 nor 17phydroxy 4- androsten-3-one (I), yields2a,7a,17a-trimethy1-l9-n0rl7f3-hydroxy-4-androsten-3-one (1).

Example 3 .7oc,1 7a-dimethyl-1 7B-lzydl'0xy-4-andr0sten- 3-oneI7-acetate (I) A solution of 10 g. of 7a,17a-dimethyl-17/3-hydroxy-4-androsten-3-one (I) in 20 ml. of acetic anhydride and 50 ml. of pyridinewas refluxed under nitrogen for about 16 hours. The solvent was removedon a rotary evaporator leaving a brown crystalline residue. It wastriturated with Skellysolve B, the crystals washed with Skellysolve Band methanol, and recrystallized from acetone-Skellysolve B to give 5 g.of product melting at 187 to 191 C. Part of the product wasrecrystallized from acetone-Skellysolve B to give an analytical sampleof 7a,17a-dimethyl- 17l3-hydroxy-4-androsten-3-one l7-acetate (I);melting point to 192 C.;

Mfg, 242 m (e=16,750); [GAD-{"900 (chloroform) A1talysis.CalCd. for C HO C, 77.05; H, 9.56. Found: C, 76.85; H, 9.68.

Following the procedure of Example 3 but substitutingZaJa-dimethyl-17B-hydroxy-4-androsten 3 one (I) and 20t,70c,l7octrimethyl-17/3-hydroxy-4-androsten 3 one as starting materials, yieldsthe corresponding 17-acetates Example4.2a,7a,-dimethyl-17,8-hydroxy-4-andr0szen-3- one 1 7 -ac tate(20c,7oc-dil71GIhyItESIOSIBI'OIZ6 1 7-acetate) (a) A solution of 1 g. of2a,7a-dimethyl-17,8-hydroxy- 4-androsten-3-one (1), dissolved in 6 ml.of dried and redistilled pyridine, is treated with 6 m1. of aceticanhydride. After standing at room temperature for about 17 hours, thereaction mixture is poured into ice water. The mixture is filtered afterabout two hours of standing and the precipitate washed with water anddried in vacuo. Upon recrystallization from a mixture of acetone andhexane, pure 2a,7a-dimethyl-17B-hydroxy-4-androsten-3- one l7-acetate(I) is obtained.

2a,7oz,l7a trimethyl-l7B-hydroxy-4-androsten-3-one 17- benzoate (207a,17a-trimethyltestosterone 17-benzoate) (b) A suspension of 0.3 g. of2a,7a,17a-trimethyl-17,8- hydroxy-4-androsten-3-one (I) in 12 ml. ofbenzene is treated with 0.3 ml. of distilled benzoyl chloride and 0.3ml. of dry pyridine. The mixture is stirred for about 17 hours at roomtemperature. After washing with aqueous dicarbonate and drying, thesolution is chromatographed over Florisil. The fractions containingbenzoate ester by ultraviolet examination are combined andrecrystallized from ethyl acetate and hexane to give pure2a,7oz,17octrirnethyl-17/3-hydroxy-4-androsten 3 one 17 benzoate (I).

In the same manner as given in Example 4 (a and b), the17[3-cyclopentylpropionate, formate, butyrate, isobutyrate, valerate,isovalerate, hexanoate, octanoate, phenylacetate and other like17-esters of 2a,7 x-dimethyl and 20,7cx,17a-trimethyltestosterone (I)are prepared by the reaction of their corresponding 1713 alcohols withthe appropriate acid anhydride or halide.

Similarly, following the procedures of Example 4 (a and b) and theparagraph directly above, the following representative 17B-hydroxycompounds are converted to a desired 17-ester named therein:

(1) 201,7 a-dimethyl-19-nor-17B hydroxy 17a-ethynyl-4- androsten-3-one(I) and (2 2a,7a,17u-trimethyl-19-nor- 17fl-hydroxy-4-androsten- 3-one(I).

Example 5 .7x-methyl-1 9-rz0r-1 7 13-lzydr0xy-1 7tethynyl-4-amirosten-3-0ne (III) (a) 7a-methyl-19-nor 4androstene-3,17-dione-3-pyrrolidinyl enamine.

To a solution of 10 mg. of 7a-methyl-l9-nor-4-androsten-3,17-dione (II)(prepared as in Belgian Patent 610,385) in a small volume of boilingmethanol, several drops of pyrrolidine were added. The resultingsolution was concentrated by evaporation and allowed to cool. Thecrystalline solid which separated was isolated by filtration, washedwith a small volume of methanol and dried. There was thus obtained7oc-methyl-19-nor-4-androsten-3,l7-dione 3-pyrrolidinyl enamine in theform of crystalline solid melting at 151 to 160 C. The intravioletabsorption spectrum of the compound (in ether solution) exhibited amaximum at 282 III/L (e=23,45t)). The infrared absorption spectrum (in amineral oil mull) and 1935 cmf (b) 7a-methyl-19-nor-l7fihydroxy-17a-ethynyl-4-androsten-3-one (III) A volume of 1 ml. of a 20percent by weight suspension of sodium acetylide in xylene wascentrifuged and the solid that separated was taken up in 6 ml. ofredistilled dimethyl sulfoxide. To the resulting mixture was added the-3-pyrrolidinyl enamine from 0.5 g. of7a-rnethyl-19-nor-4-androstene-3,17-dione, prepared as described in (a),above. The mixture so obtained was maintained under an atmosphere ofnitrogen for about hours, after which time the excess sodium acetylidewas destroyed by dropwise addition of water. About 2 ml. of water and 5ml. of methanol was added to obtain a clear solution which was thenheated on a steam bath for 1 hour. The mixture so obtained was extractedwith ether and the ethereal extract washed successively with dilutehydrochloric acid, dilute sodium carbonate, and water, then dried overanhydrous magnesium sulfate. The dried solution was filtered and thefiltrate evaporated to dryness. The residue was triturated with amixture of ether and Skellysolve B and recrystallized twice from amixture of acetone and Skellysolve B. There was thus obtained 0.161 g.of 7a-methyl-19-nor-17fl-hydroxy-l7a-ethynyl-4-androsten-3-one (III)with a melting point of 197 to 199.5 C.;

x3933? 240.5 m 113,132 3,390, 3,240, 2,100; 1,663 and 1,623 emfAnalysis.-Calcd. for C H O C, 80.72; H, 9.03. Found: C, 80.44; H, 9.05.

If desired, the crude product can be chromatographed prior tocrystallization.

Following the procedure of Example 5 but substituting2a,7x-dimethyl-19-nor-4-androstene-3,l7-dione (II) and2a,7ot-dimethyl-4-androstene-3,l7-dione (II) for the starting materialemployed therein, yields, respectively,

(a) 2a,7a-dimethyl-l9-nor-4-androstene-3,17-dione 3- pyrrolidinylenamine and 2a,7a-dimethyl-4-androstene- 3,17-dione 3-pyrrolidinylenamine and (b) .2u,7ot-dimethyl-19-nor-17B hydroxy-17ot-ethynyl-4-androsten-3one (III), b h-dimethyl-17fi-hydroxy-17a-ethynyl-4-androsten-3-one (III).

Following the procedure of Example 5 but substituting the followingreagents for sodium acetylide:

(1) sodium methylacetylide,

( 2) sodium chloroacetylide,

(3) sodium bromoacetylide and (4) sodium trifluorornethylacetylide,

G .1 y elds, I GSPGCIIVGIV,

( 1) 7ot-rnethyl-19nor-17fl-hydroxy- 17a-( 1-propynyl)-4-androsten-3-one (III),

(2) 7a-methyll9-norl7fi-hydroxy-17a-chloroethynyl- 4-androsten-3-one(III),

(3) 7u-methyl-l9-nor-17fi-hydroxy-l7a-bromoethynyl- 4-androsten-3-one(III) and (4)7a-n1ethyl-19-nor-l7fi-hydroxy-17a-trifluoromethylethynyl-4-androsten-3-one(III).

Following the procedure of Example 5 and the two hereinabove paragraphsyields:

(1) 2a,7u-dimethyl-19-nor-17p-hydroxy-17ot- (l-propynyl-4-androsten-3-one (III) (2) ZaJa-dimethyI-17fi-hydroxy-17a(1-propynyl)-4-androsten-3-one (III),

(3)2a,7a-dimethyl-19-nor-l7fl-hydroxy-l7a-chloroethynyl-4-androsten-3-one(III),

(4) 20;,7a-dimethyl-Ufl-hydroxy-l7a-chloroethynyl- 4-androsten-3-one(III),

( 52a,7x-dimethyl-l9-nor-17fi-hydroxy-17u-bromoethynyl-4-androsten-3-one(III),

(6) 2a,7u-dimethyl-l7B-hydroxy-17a-bromoethynyl- 4-androsten-3-one(III),

(7)2a,7a-dimethyl-l9-nor-17B-hydroxy-l7a-trifluoromethylethynyl-4-androsten-3-one(III) and (8)2a,7a-dimethyl-17fi-hydroxy-l7a-trifiuoromethyl-4-androsten-3-one (III).

Following the procedures of Example 5 and the subsequent two paragraphs,but substituting the respective 3-enamine, 3-ketal or 3-enol ether ofthe following starting materials prepared from the corresponding3-ketosteroid, e.g., in the manner disclosed in J. Amer. Chem. Soc. 7-8,430, ibid. 80, 4717 and ibid. 75, 650, respectively;

(a) I 7a-methyl-4-androstene-3,17-dione (II),

(b) 7ct-methyl-19-nor-4-androstene-3,17-dione (II),

(c) 2a,7a-dimethyl-4-androstene-3,17-dione (II) and (d)2a,7a-dimethyl-l9-nor-4-androstene-3,17-dione (II),

followed by cleavage of the aforesaid protecting group at the 3-positionto restore the 3-keto function (in the manner described in theabove-cited publications), yields, respectively,

(a) (1) 7a-methyl-17B-hydroxy-17a-ethynyl- 4-androsten-3-one (III),

(a) (2) 7a-methyl-17fi-hydroxy-l7a(1-propynyl)- 4-androsten-3-one (III),

(a) (3) 7a-rnethyl-17 8-hydroxy-17a-chloroethynyl- 4-androsten-3-one(III),

(a) (4) 7a-methyl-17B-hydroxy-l7a-bromoethynyl- 4-androsten-3-one (1H),

(a) (5) 7a-methyl-173-hydroxy-17B-trifluoromethylethynyl-4-androsten-3-0ne (III),

(b) (1 7a-methyl-19-nor-l7/3-hydroxy-17ot-ethynyl- 4-androsten-3-one(HI),

(b) (2) 7a-rnethyl-19-nor-17B-hydroxy-17ul-propynyl -4-androsten-3-one(III),

(b) (3) 7a-methyl-19-nor-17B-hydroxy-17u-chloroethynyl-4-androsten-3-one(III),

(b) (4) 7a-methyl-l9-nor-17B-hydroxy-l7a-bromoethynyl-4-androsten-3-one(III),

(b) (5)7a-methyl-l9-nor-17,8-hydroxy-17atrifluoromethylethynyl-4-androsten-3-or1e(III),

(c) (1) 2a,7a-dimethyl-17 8-hydroxy-17a-ethynyl-4- androsten-3-one(III),

(c) (2) 2a,7u-dimethyl-17,6-hydroxy-17u-(l-propynyl- 4-androsten-3-one(III),

(e) (3) 2u,7a-dimethyl-l7 9-hydroxy-17a-chloroethynyl- 4-androsten-3-one(III),

(c) (4) 2a,7a-dimethyl-17(3-hydroxy-17a-bromoethynyl- 4-androsten-3-one(III),

(c)2a,7ot-dirncthyl-17,8-hydroxy-17ot-trifiuoromethylethynyl-4-androsten-3-one(III),

(d) (2) 2m,7a-dimethyl-l9-nor-17fi hydroxy-17a-(1-propynyl)-4-androsten-3-one (III),

(d) (3) 2a,'7o-dimethyl-19-nor-17/8-hydroxy-17achloroethynyl-4-androsten-3-0ne (III),

(d) (4)2u,7a-dimethyl-l9-nor-l7B-hydroXy-l7abromoethynyl-4-androsten-3-one(III) and (d) (5)ZtxJQt-dimethyl-19-nor-17fl-hydroxy-17e-trifluoromethylethynyl-4-androsten-3-one(III).

A suspension of 90 mg. of 1 percent palladium on carbon catalyst in 50ml. of dioxane (purified as described in Fieser, Methods of OrganicChemistry, page 368, 2nd

edition) was saturated with hydrogen at atmospheric pres- 2 sure. To thedioxane suspension 300 mg. of 7a-rnethyl-19-nor-17/i-hydroxy-17a-ethynyl-4 androsten 3 one (III), prepared as inExample 5(b), was added and hydrogenated at atmospheric pressure untiltwo equivalents of hydrogen was consumed. The reaction mixture wasfiltered through a bed of Celite (diatomaceous earth), the filtrateconcentrated to dryness and chromatographed through a 100 g. column ofFlorisil packed wet with Skellysolve B. Elution by a gradient techniqueemploying between 4 l. of 2 percent acetone Skellysolve B and 4 l. of 8percent acetone Skellysolve B collecting 250 ml. fractions, gave thedesired product as an oil infractions 21 to 30. The oil was crystallizedtwice from a mixture of Skellysolve B and ether to give 160 mg. of7a-methyl-19-nor-17fi-hydroxy-l7a-ethyl-4-androsten-3-one (IV), meltingat 132 to 135 C.

A112 241 my 11,200)

An analytical sample from another run melted at 138 to 139 C.

Analysis.Calcd. for C l-1 0 C, 79.69; H, 10.19. Found: C, 79.42; H,10.23.

Following the procedure of Example 6 but substituting h the followingcompounds for the starting material employed therein:

(a) 7a-methyl-17fi-hydroxy-17a-ethynyl-4 androsten- 3-one (III),

(b) ZaJa-dimethyl-I7fi-hydroxy 17cc cthynyl4-androsten-3-one (III) and(c) 2a,7a-dimethyl-19nor 17B -hydroxy 17a ethynyl-4-androsten-3-one(III), yields the corresponding 17a-ethyl counterparts of(a), (b), (c),and (d) of Formula 1V.

Following the procedure of Example 6 but substituting the followingcompounds for the starting material employed therein:

yields, respectfully,

(l) 7a-rnethyl-17B-h -'droxy-17a-(3-propy1)-4-androsten- 3-one (IV),

(2) 7ot-methyl-17,9-hydroxy-17u-trifiuoromethyl-4- androsten-3-one (IV),

(3) 7a-methyl-19-nor-17fi-hydroxy-17a-(3-propyl)-4- androsten-3-one(IV),

(4) 7a-methyl-19-nor-17fl-hydroxy-17a-trifluoromethyl- 4-androsten 3one(IV),

(5) ZaJa-dimethyI-I7,6-hydr0xy-17a-(3-propyl)-4- androsten-3-one (IV),

(6) ZaJa-dimethyl-17B-hydroxy-17a-trifiuoromethyl-4- androsten-3-one(IV),

(7) 2a,7a-dimethyl-19-nor-175-hydroxy-17a-(3- propyl)-4-androsten-3-one(IV) and (8)ZuJa-dimethyl-19-nor-17fi-hydroxy-17ot-trifiuoromethyl-4-androsten-3-one(IV).

A solution of 2 g. of 7tx-methyl-l9-nor-4-androstenc-3,17-dione-3-pyrrolidyl enamine (II) (prepared as in Example 5(a), abovein m1. of 2 N methylmagnesium bromide in a mixture of equal volumes ofbenzene and tetrahydrofuran, is heated under reflux for about 18 hoursto yield 7a,17e-dimethyl-19nor-17(3-hydroxy 4 andro sten-3-one3-pyrrolidyl cnamine. The 3-enamine function is hydrolyzed to yield thecorresponding free 3-ketone in the manner described in Example 5(b),above. The desired product is eluted and crystallized from aqueousacetone to give 7a,17u-dimethyl-19-nor-17B-hydroxy-4-androstcn-3-one(V).

Following the procedure of Example 7 but substituting formethylmagnesium bromide, the following Grignard reagents:

yields, respectively,

(1) 7a-methyl-Nix-ethyl-19-nor-l7fl-hydroxy-4- androsten-3-one (V),

(2) 7a-methyl-17a-n-propyl-19-nor-17B-hydroxy-4- androstcn-3-one (V),

(3) 7a-methyl-17a-i-propyl-19-n0r-17li-hydroxy-4- androsten-3-one (V)and (4) 7ot-methy1-17tx-n-butyl-19-nor-17fi-hydroxy4- androsten-3-one(V).

ethylmagnesium bromide (or chloride), n-propylmagnesium bromide (orchloride), i-propylmagnesium bromide (or chloride) and, n-butylmagnesiumbromide (or chloride),

Following the procedures of Example 7 and the paragraph immediatelypreceding the present one, reaction of the following pairs of startingmaterials and followed by hydrolyzing the products with a base, yields,respectively,

(1 7u-methyl-17a-ethyl-19-nor-17p-hydroxy-4- androsten-3-one (V),

(2) 7e-methyl-17u-n-propyl-17/3-hydroxy-4-androstcin 3-one (V),

(3) 211,70,17ot-trimethyl-19-nor-17fl-hydroxy-4- androsten-3-onc (V) and(4) 2a,7 z,17ot-trimethyl-17B-hydroxy-4-androsten-3- one (V),

Following the procedure of the Example 7 and the paragraph thereafter,reaction of the following pairs of starting materials and Grignardreagents:

(1) 7a-methyl4-androstene-3,17-dione (II) and isopropyl magnesiumbromide,

(2) 7u-methyl-4-androstene-3,17-dione (II) and nbutyl-magnesium bromide,

(3) 2a,7a-dimethyl-l9-nor-4-androstene-3,17-dione (II) andmethylmagnesium bromide, and

(4) 2a,7a-dimethyl-4-androstene-3,17-di0ne (II) and ethylmagnesiumbromide,

yields, respectively,

(1) 7a-methyl-17u-isopropyl-17B-hydroxy-4-androsten- 3-one (V),

(2) 7u-methyl-17a-n-butyl-175-hydroxy-4-androsten- 3 one (V),

(3) 2a,7u,17a-trimethyl-19-nor-17fl-hydroxy-4- androsten-3-one (V) and(4) 2a,17a-dimethyl-17u-ethyl-17fi-hydroxy-4- androsten-3-one (V).

The 7u-rnethyl (and 2a,7a-dimethyl)-l7o-alkyl-17,B- hydroxy compounds(V) produced in Example 7 and the three paragraphs immediately above,can be converted to their corresponding 17-acylates by following theprocedures of Example 4 and the paragraph thereafter.

Example 8.-7a-methy[-3,5-andr0stadiene-3,17B-di0l 3,17-diacetate (Ia) Asolution of 1 g. of 7a-methyl-17,8-hydroxy-4-androsten-3-one (I)(prepared as in J. Amer. Chem. Soc., 81 4069), 100 mg.,ofparatoluenesulfonic acid and ml. of acetic anhydride in 40 ml. oftoluene was heated at reflux under nitrogen for about 4.5 hours. Thesolvent was evaporated with a stream of nitrogen and the crystallineresidue triturated with a small amount of aqueous methanol to yieldcrystal 7tx-methyl-3,5-androstadiene-3, 17fi-diol 3,17-diacetate (Ia).

Example 9.7u-methyl-19-n0r-3,5-andr0starliene- 3,17,8-di0l3,17-a'iacetate (Ia) A solution of 1 g. of 7a-methyl-l9-nor-l78-hydroxy- 4-androsten-3-one (I) (prepared as in Example 28 of BelgianPatent 610,385), 40 mg. of paratoluenesulfonic acid, 8 ml. of aceticanhydride in ml. of toluene was refluxed under nitrogen for about 5hours. Most of the solvent was removed with a stream of nitrogen to givea sticky precipitate. A few milliliters of methanol containing a fewdrops of pyridine was added to the precipitate to yield loose crystalswhich were filtered immediately, washed with cold methanol and dried toyield 0.9 g. of the desired enol acetate (Ia). This product wasrecrystallized by dissolving in methylene chloride and diluting withmethanol at room temperature to give pure 7m methyl l9nor-3,5-androstadiene-3,17fl-diol 3,17- diacetate (Ia) having a rotation[m1 of 122 (chloroform) and ris. (e=19,250

Analysis.Calcd. for =C H O C, 74.16; H, 8.66. Found: C, 73.69;H, 8.40.

Example 10.7ot,17a-dimelhyl3,5-andr0.s'zadiene- 3,17fl-diol3,17-diacetate (Ia) A solution of 1 g. of70,17u-dirnethy1-17a-hydroxy-4- androsten-3-one 17-acetate (I) preparedas in Example 3), 100 mg. of paratoluenesulfonic acid and 10 ml. ofacetic anhydride in ml. of toluene was heated at reflux under nitrogenfor about 4.5 hours. The solvent was then removed with a stream ofnitrogen to leave a residue that was triturated with Skellysolve B. Twocrops of crystals were obtained from the Skellysolve B. The combinedcrops were triturated with methanol and removed most of the color togive 0.57 g. of 70,l7a-

dimethyl 3,5 androstadiene-S,17a-diol 3,17-diacetate (Ia) having Age,234.5 mg ($20,450 244 my (e=15,650)

with a shoulder at 230 my.

If desired the crude product is chromatographed prior tocrystallization.

Following the procedures of Examples 8, 9 and 10 but substituting foracetic anhydride another anhydride or acid chloride, such as propionic,butyric, valeric, hexanoic, trimethylacetic, isobutyric, isovaleric,cyclohexanecarboxylic, p hexylpropionic, benzoic, phenylacetic,phenylpropionic, acrylic, crotonic, undecylenic, propiolic, andcinnamic, yields, respectively, the corresponding 7ozmethyl-3,5-androstadiene-3,17B-diol 3,17- diacylate (Ia), 70c methyl19-nor-3,S-androstadiene- 3,17fi-diol 3,17-diacylate (Ia) and7u,17a-dimethyl-3,5- androstadiene-3,175-di0l 3,17-diacylate (Ia).

Following the procedures of Examples 8, 9 and 10 but substituting forthe starting steroids employed therein the following representativecompounds:

(1) 2a,7a-dimethyl-l7,8-hydroxy-4-androsten-3-one (I),

(2) 2a,7a-dimethyl-19-nor-17,8-hydroxy-4-androsten-3- one (I),

(3) 20,7a,17a-trimethyl-17,8-hydroxy-4-androsten-3- one (I),

( 4) 7a,17a-dimethyl-19-nor-175-hydroxy-4-androsten- 3-one (I),

(5 7a-methyl-19-nor-17p-hydroxy-17a-ethynyl-4- androsten-3-one (III),

(6) 7u-methyl-17 3-hydroxy-l7a-ethynyl-4- androsten- 3-one (III),

(7 7ot-methyl-19-nor-17B-hydroxy-17a-( 1-propynyl)- 4-androsten-3-one(III),

(8) 7a-methyl-17,8-hydroxy-17a-trifluorornethylethynyl-4-androsten-3-one (III),

(9) ZaJa-dimethyl-17,8-hydroxy-17a-chloroethynyl-4- androsten-B-one(III),

(10)2a,7a-dimethyl-19-nor-17B-hydroxy-17u-bromoethynyl-4-androsten-3-one(III),

(12) 7a-methyl-17fl-hydroxy-17ot-n-propyl-4-androsten- 3-one (IV),

( 13) 7a-methyl-19-nor-17,8-hydroxy-17a-trifiuor0methyl-4-androsten-3-one (IV),

(14) 2a,7ot-dimet hyl-19-nor-17a-hydroxy-17otethyl-4- androsten3-one('IV),

( 15) 2a,7a-dimethyl-17B-hydroxy-17a-ethyl-4- androsten-3-one (IV),

('16) 2a,7a-dimethyl 17a-ethyl 19-n orl7B-hydroxy-4- androsten-3-one (V)and (17) =2a,7a-dimethy:ll7a-n propyl-17,8-hydroxy-4- androsten-3-one(V),

yields, respectively,

(1) 2a,7a-dirnethyl3,5-androstadiene-3 l7/3-diol 3,17diacetate (Ia),

(2) 2,8,75dimethy-l-l9-nor-3,5=nndrostadiene-3,l7/3-diol 3,17-diac6tate(Ia),

(3) 2a,7a,l7a-trimethyl-3,5-androstadiene-3,17B-diol 3,1 7-diacetate('la),

(4) 7a,l7ot-dimethyl-l9-nor-3,5-androstadiene-3,17,8-diol 3,17-diacetate(Ia),

(5) l7a-ethynyl7a-methyl-19-nor-3,S-androstadiene- 3,17B-diol3,17-diaceta-te IIIa),

6) 1:7,B-et'hynyl-7e-methyl-3,5-androstadiene-3 l7/3-diol 3,17-diacetate(T1142),

(7) 7;8-methyl-d7a-propynyl-l9-nor-3,S-an'drostadiene- 3,17fi-diol3,17-diacetate (Ilia),

(9) 17fi-chloroethynyl-2a,7a-dimethyl-3,5-

androstadiene-ll7,8-diol 3,17-diacetate (Illa),

(10) l.7a-br-omoethynyl-2a,7a-dimethyl- 19-nor-3,5- androstadiene-G,l78-diol 3,17-diacetate (H la),

( l'l) l-7a-ethyl-7a-methyl-19-nor-3,5-a-ndrostadiene-3,

17fl-di'o1 3, l7-diacetate ('IVa),

( 1 2) 7a-methyl-17a-npropyl-3,S-androstadiene-B,17B-

diol 3,17-diacetate (IVa),

(13) 7a-methyl-17a-trifiuoromethyl ethynyl-l9-nor-3,5-

=androstadiene-3, 17 8-diol 3,17-diacetate IVa) (14)17a-ethyl-2a,7a-dimethyl-19-nor-3,S-androstadiene- 3,17fidiol3,17-diacetate (IVa),

( 15) 17a-ethyl-2a,7a-dimethyl-3,S-androstadiene-3,17(3- diol3,17-diacetate (Na),

(16) '2a,-7a-dimethyl-17a-ethyl-19-nor-3,S-androstadiene- 3,17 3-di0l3,17-diacetate (Va) and ("17)2a,7a-dimethyl-l7a-n-propyl-3,5-audrostadiene-3,

17fi-diol 3, 17-diacetate (Va).

Similarly, by following the procedures of the two preceding paragraphsand reacting the A -3-keto starting materials of (1) through (17) of theimmediately preceding paragraph with the appropriate hydrocarboncarboxylic acid anhydride instead of acetic anhydride employed toprepare the products of (1) through (17) there are produced thecorresponding 3,5-andro'stadiene 3,17-diacylates of (1) through (17)such as the 3, 17-dibutyrate, 3,17-divalerate, 3,-17-dihexanoate,3,17-ditrimethylacetate, 3,17-diisobutyrate, 3,17-diisovalerate3,-17-dicyclohexanecarboxylate, 3,17-dicyclopentylpropionate,3,17-di-phexylpropionate, 3,17-dibenzoate, 3,17-diphenylacetate,3,l7-diacrylate, 3,17-dicrotonate, 3,17-diundecylanate, 3,17-dipropiolate, and 3,17-dicinnamate.

Example 11.-7x,1 7a-aimethyl-3,5-androstadien2-3,] 7,8-di/zydrxy-3-acctate (Ia) To a solution of 100 ml. of tetrahydroturan(purified by percolation through an alumina column) cooled in an icebath, 25 ml. of ethereal 3 M methyl magnesium bromide and 1.5 g. ofcuprous chloride are successively added. A solution of g. of17a-methyl-17,B-hydroxy-4,6- androstadien-3-one (prepared as in J. Amer.Chem. Soc., 81, 4069) in 120 ml. of tetrahydrofuran (purified as above)is added slowly with stirring. The whole operation is done undernitrogen. After about 5 minutes, 20 ml. of acetic anhydride in 20 ml. oftetrahydrofuran (also purified as above) are slowly added. The mixtureis stirred for about an additional 2.5 hours; 100 ml. of ether are addedand 3 N hydrochloric acid saturated with sodium chloride (well purgedwith nitrogen to remove all traces of oxygen) are carefully added to themixture. The organic phase is washed again with nitrogen purged 3 Nhydrochloric acid saturated with sodium chloride, saturated sodiumchloride solution, 5% sodium hydroxide solution saturated with sodiumchloride and finally with saturated sodium chloride solution untilneutral. The solution is dried over sodium sulfate and concentrated todryness. The crude residue is purified by chromatography to yield 7a,17udimethyl-3,5-and'rostadiene-3,17 3-dihydroxy 3- acetate Ia).

Following the procedure of Example 11 but substituting for aceticanhydride another anhydride, such as propionic, butyric, valeric,hexanoic, trime-thylacetic, isobutyric, isovaleric,cyclohexanecarboxylic, p-hexylpropionic, benZoic, phenylacetic,phenylpropionic, acrylic, crotonic, undecylenic, propiolic, andcinnamic, yields the corresponding7a,17a-dimethyl-3,5-androstadiene-3,17,8- dihydroxy 3 monoacylate (Ia).

Following the procedure of Example 11 but substituting for17a-methyll7B-hydroxy-4, 6-androstadien-3-one the followingrepresentative starting materials:

('1) 17B-1nethyl-19'-nor-17p-hydroxy-4,6-androstadien-3-one,

(2) 2a,17a-dimethyl-17,8-hydroxy-4,6-androstadien-3-one,

(3) 2a,17a-dimethyl-19-nor-17/3-hydroxy-4,6-androstadien-3-one,

(4) 4,6-and1ostadien-3,17-dione,

(5) 19-nor-4,6-androstadien-3,l7-dione,

(6) 2a-methyl-4,6-androstadien-3,17-dione,

(7) 2a-rnethyl-19-nor-4,6-androstadien-3,17-dione,

(8) 17B-hydroxy-17a-ethynyl-4,6-androstadien-3-one,

(9) Za-methyl-l9-nor-17fi-hydroxy-17a-ethynyl-4,6-

androstadien-3-one,

(10) 17fi-hydroxy-17a( l-propynyl)-4,6-androstadien- 3-one,

(11) 17f3-hydroxy-17a-trifluoromethylethynyl-4,6-

androstadien-S-one,

( 12) 2a-methyl- 17 B-hydroxy- 17a-chloroethynyl-4,6-androstadien-3-one,

(13) 2a-methyl-19-nor17p-hydroxy- 17oc-b1'0m0-ethynyl-4,6-androstadien-3-one,

( 14) 19-nor-17fi-hydroxy-17a-ethyl-4,6-andr0stadien-3- one,

'( 15) 17 B-hydroxy- 1 7oz- (n-propyl) -4,6-androstadien- 3 -one,

(16) 19-nor-17/3-hydroxy-17a-tri[iuoromethyl-ethynyl- 4,6-androstadien-3-one,

(17) 17a-ethyl-19-nor-17,8-hydroxy-4,6-androstadien- 3 -one and (18)Zu-methyl-I7a-n-pr0py1-17/3-hydroxy-4,6-androstadien-3 -one,

yields, respectively,

1 1) 7a-methyl-17a-trifiuoromethylethynyl-3,5-

androstadiene-3,17,B-diol S-acetate (IIIa) (12)17a-4-chloroethynyl-2u,7a-dimethyl-3,5-androstadiene-3,17fl-diol3-acetate (IIIa),

(13) 17a-hrornoethynyl-2a,7a-dirnethyl-3,5-androstadiene-3, 17fi-diol3-acetate (IIIa),

(14) 17a-ethyl-7a-methyl'19-nor-3,5-androstadiene- 3,17B-diol 3-acetate(IVa),

(15) 7a-methyl-17a-(n-propyl) -3,5-androstadiene- 3,17/8-diol 3-acetate(Na),

(16) 7a-methyl-17a-trifluoromethylethynyl-19-nor-3,5-androstadiene-3,17,8-diol 3-acetate (Na),

(17) 17u-ethyl-7u-methyl'19-nor-3,5-androstadiene- 3,17,8-diol 3-acetate(Va) and (18) 2a,7a-dimethyl-17a-n-propyl-3,S-androstadiene- 3,17fl-diol3-acetate (Va).

Similarly, by following the procedures of the preceding two paragraphsand reacting the A -3-keto starting materials of (1) through (18) of theimmediately preceding paragraph with the appropriate hydrocarboncarboxylic acid anhydride in the manner described in Example 11, thereare produced the corresponding 3,5-androstadien 3-acylates of (1)through (18).

Example 12.-7a-methyl-3,5-andr0stadicne-3,17olzydroxy 3,17-diacetate(Ia) To a solution of ml. of tetrahydrofuran (purified by percolationthrough an alumina column) cooled in an ice bath, 25 ml. of ethereal 3 Mmethyl magnesium bromide and 1.5 g. of cuprous chloride are successivelyadded. A solution of g. of 17l3-hydroxy-4,6-androstadien-3-one (preparedas in J. Amer. Chem. Soc., 81, 4069') in 120 ml. of tetrahydrofuran(purified as above) is slowly added with stirring. The whole operationis done under nitrogen. After about 5 minutes, 20 ml. of aceticanhydride in 20 ml. of tetrahydrofuran (also purified as above) isslowly added. The mixture is stirred for about an additional 2.5 hours;100 ml. of ether is added and 3 N hydrochloric acid saturated withsodium chloride (well purged with nitrogen to remove all traces ofoxygen) is carefully added to the mixture. The organic phase is washedagain with nitrogen purged 3 N hydrochloric acid saturated with sodiumchloride, saturated sodium chloride solution, 5% sodium hydroxidesolution saturated with sodium chloride and finally with saturatedsodium chloride solution until neutral. The solution is dried oversodium sulfate and concentrated to dryness. The crude residue ispurified by chromatography to yield 70: methyl 3,5 androstadiene-"a',17B-hydroxy 3,17-diacetate (Ia).

Following the procedure of Example 12 but substituting for aceticanhydride another anhydride, such as propionic, butyric, valeric,hexanoic, trirnethylacetic, isobutyric, isovaleric,cyclohexanecarboxylic, p-hexylpropionic, benzoic, phenylacetic, acrylic,crotonic, undecylenic, propiolic, cinnamic, and yields the corresponding7a-methyl-3,5- androstadiene-Ia, 17 ,8-dihydroxy-3,17-diacy1ate (Ia).

Following the precedure of Example 12 but substituting for17,8-hydroxy-4,6-androstadien-3-one the following representativestarting materials:

( 1) 19-nor-17fi-hydroxy-4,6-androstadien-3-one, (2)Zu-methyl-17fl-hydroxy-4,6-androstadien-3-one, (3)2a-l9-nor-17B-hydroxy-4,6-androstadien-3-one,

yields, respectively,

( 1) 7a-methyl-19-nor-3,5 -androstadiene-3,1713-dio1 3,17-diacetate(Ia),

(2) 2a,7ot-dimethyl-3,5-androstadiene-3,173-diol 3,17-diacetate (Ia),and

(3) ZaJa-dimethyI-19-nor-3,5-androstadiene-3,1713-diol 3,17-diacetate(Ia).

Similarly, by following the procedures of the preceding two paragraphsand reacting the A -3-keto starting materials of (1) through (3) of theimmediately preceding paragraph with the appropriate hydrocarboncarboxylic acid anhydride in the manner described in Example 12, thereare produced the corresponding 3,5-andr-ostadien 3,11-diacylates of (1)through (3).

Example 13 .3-ethoxy-7a-methy l l 9-n0r-3 ,5 androstadieni 7 -one (Ila)To a 5 l., S-necked, round-bottom flask equipped with stirrer, condenserand heating mantle, there are added 750 g. of the known compound,7a-methyl-19-n0r-4-androstene-3,l7-dione (II), 1875 ml. of triethylorthoformate and 37.5 g. of p-toluenesulfonic acid. The reaction mixtureis heated to reflux temperature and 300 ml. of condensate removed over aperiod of about 30 minutes. Heating at reflux is continued for about anadditional 15 minutes (until the reaction goes to completion), afterwhich the reaction mixture is allowed to cool to a temperature of about40 C. About 1.5.1 of Skellysolve B (hexane hydrocarbons) are slowlyadded to the reaction mixture during vigorous stirring. After standingat between 5 to 10 C. for a period of about hours the product iscollected on a Buchner funnel by vacuum filtration, washed with about500 ml. of Skellysolve B and dried under vacuum to yield pure3-ethoxy-7a-methyl-l9- nor-3,5-androstadien-17-one (Ila).

Following the procedure of Example 12 but substituting other trialkylorthoformates for triethyl orthoformate 18 yields the corresponding3-alkoxy-7a-methyl-19-nor-3,5- androstadien-l7-one (Ha).

Following the procedure of Example 13 but substituting for 7ainethyl-19-nor-4-androstene-3,17-dione (II) the following representativestarting materials:

(1) 2a,7a-dimethyl-17B-hydroxy--4-androsten-3-one (I),

(2) 2a,7a-dimethyl-19-nor-17 fi-hydroxy-4-androsten- 3-one (I),

(3) 211,7 a, 17 a-trimethyl- 17 fi-hydroxy-4-androsten-3- one (I),

(4) 7a,17a-dirnethyl-19-nor-17fl-hydroxy-4-androsten- 3-one (I),

(5) 7a-methyl4-androstene-3,17-dione (II),

(6) 2a,7a-dimethyl-l9-nor-4-androstene-3,17-dione (II),

(7) 2,7a-dimethyl-4-androstene-3,17-dione (II),

(8) 7a-methyl-19-nor-17,B-hydroxy-17a-ethynyl-4- androsten-3-one (III),

(9) 7 a-methyl- 17,8-hydroxy-l 7ot-ethynyl-4-and'rosten- 3-0ne (III),

(10) 7u-methyl-19-n0r-17fi-hydroxy-17a- 1-propynyl)- 4-androsten-3-one(III),

(1 1) 7a-methyl-17fl-hydroxy-17atrifluoromethylethynyl-4-androsten-3-one (III),

(12) 2a,7ot-dirnethyl-17,8-hydroxy-17a-chloroethylnyl- 4-androsten-3-one(III),

(13) 2a,7a-dimethyl- 19-nor- 17/3-hydroxy- 17oc-b1OII10-ethynyl-4-androsten-3-one (III),

(14) 7a-methyl-19-nor-17,8-hydroxy-17a-ethy1-4- androsten-3-one (IV),

(15 7 a-methyl-l7/3-hydroxy-17a- (n-propyl) -4-ar1drosten-3-one (IV),

( 16) 7a-methyl-19-nor-17fi-hydroxy-17ot-trifluoromethylethynyl-4-androsten-3-one(IV),

( l7) 7oL-1Tl61lhYl- 17a-ethyl- 19-nor- 17fi-hydroxy-4- androsten-3-one(V) and l 8) 2a,7u-dimethyl- 17 a-n-propyl- 173-hydroxy-4-androsten-3-one (V),

yields, respectively,

( I) 3-ethoxy-2a,7a-dirnethyl-3,5-androstadien-17fl-ol Ia), (2)3-ethoxy-2a,7a-dimethyl-19-nor-3,5-androstadien- 17 8-01 (la), (3 )liiet)hoxy-2a,7a,17a-trimethyl-3,5-androstadien-17B- o a (4)3-ethoxy-7a,17a-dimethyl-19-nor-3,5-androstadien- -01 (Ia), (5 )1 I3-)ethoxy-7a-methyl-3,5 -androstadien-17-one a (6)3-ethoxy-7u-methyl-19-nor-3,5-androstadien-17- one (Ha), (7-)ethoxy-2a,7a-dimethyl-3,5-androstadien-l7-one a a (8)3-ethoxy-17a-ethynyl-7a-methyl-19-nor-3,5-androstadien-17fl-o1 (II'Ia),(9) 3-ethoxy-17a-ethynyl-7a-methyl-3,5-androstadien- 175-01 (IIIa), 10)3-ethoxy-7a-methyl-17a (l-propyne)-3,5-androstadien-17fi-ol (IIIa),(1 1) 3-ethoxy-7 a-methyl-17a-trifiuoromethyl-ethynyl-3,5-androstadien-17/8-ol I'IIa), 12)3-ethoxy-17a'chloroethynyl-2a,7a-dimethyl-3,,5-

androstadien-l7B-ol (II Ia), 133-ethoxy-17,6-bromoethynyl-2u,7a-dimethyl-19-nor-3,5-androstadien-l7fi-ol (IIIa), (14)3-ethoxy-17wethyl-7a-methyl-19-nor-3,5-androstadien-l7,8-ol (Na), (15)3-ethoxy-7wmethyl-l7a-(propyl)-175-ol (Na), (16)3-ethoxy-7a-methyl-17a-trifiuoromethyl-ethynyl-19-nor-3,5-androstadien-175-01 (Na), (17) 3-ethoxy-7x-methyl-l7a-ethyl-19-nor-3,5-androstadien-17B-ol (Va), and 18)3-ethoxy-2a,7a-dimethyl17a1n-propy1-3,5-androstadien-IZB-ol (Va).

Similarly, by following the procedures of the two preceding paragraphsand reacting the A -3-keto starting materials of (1) through (18) of theimmediately preceding paragraph with the appropriate trialkylorthoformate in the manner disclosed in Example 13, there are producedthe corresponding 3,5-androstadien-3-alkoxides of (1) through (18).

As indicated heretofore, the compounds of this invention are useful intherapy for their anabolic antifertility, antiandrogenic,anti-estrogenic and hypocholes teremic (i.e., reducing bloodcholesterol) activities, and particularly in the treatment atatherosclerosis and ateriosclerosis. Adminstration to mammals, includinghumans, depends on the particular compound involved, severity of thecondition being treated and the individuals response to the medication.In general, a dose of about 5 to 1000 mg. of each of the compoundsexemplified in Examples 1-13 and embraced within Formulae Ia to Va isgiven one to three times a day, and preferably about 50 to about 500 mg.thereof one to three times a day, in the treatment of conditionsincident to the foregoing activities when incorporated in conventionalpharmaceutical compositions.

The following examples illustrate the incorporation of the activeingredients of this invention in pharmaceutical formulation.

Example 14.C0mpressed tablets A lot of 10,000 compressed tablets, eachcontaining mg. of 7a-methyl-3,5-androstadiene-3,17B- ihydr0xy3,17-diacetate is prepared from the following ingredients:

7a-methyl-3,5-androstadiene-3,17B-dihydroxy 3,17-

diacetate 100 Dicalcium phospate 2500 Methylcellulose, U.S.P. cps.) 65Talc, bolted 450 Calcium stearate, fine powder Example 15.Hard gelatincapsules A lot of 1000 hard gelatin capsules, each containing 100 mg. of7a,l7a-dimethyl-3,5androstadiene-3,17j8-dihydroxy 3,17-diacetate isprepared from the following ingredients:

7a,17a dimethyl 3,5-androstadiene 3,17,8-dihydroxy 3,17-diacetate 100Lactose 150 Calcium stearate 2 Talc 3 The lactose, talc and stearate aremixed well and the 711,170: dimethyl 3,5-androstadiene-3,l7fi dihydroxy3,17-diacetate incorporated into the mixture. The whole is mixed welland filled into two-piece hard gelatin capsules.

The capsules are used in the reduction of cholesterol levels in adulthumans at a dose of 36 capsules daily.

Example 16.S0fl gelatin capsules A batch of 1000 soft gelatin capsules,each containing mg. of 2a,7a-dirnethyl-3,5-androstadiene-3,17fi-di- 20hydroxy 3-acetate and corn oil is prepared from the following materials:

ZaJu-(llmfilhYl 3,5 androstadiene-3,17/3-dihydroxy 3-acetate, micronized-..gm 50 Corn oil q.s.

A uniform dispersion of the active ingredient in the corn oil isprepared and the dispersion filled into soft gelatin capsules byconventional means.

One capsule is given three times a day in the treatment ofhypercholesteremia in adult humans.

Example I7.Aque0us oral suspension An aqueous oral suspension containingin each 5 ml. 500 mg of 7a-methyl-3,5-androstadien-3-ethoxy-17fi-ol isprepared from the following materials:

7a-methyl 3,5 androstadien 3-ethoxy-l7B-ol,

micronized gm 1000 Methylparaben, U.S. P. gm 7.5 Propylparaben, U.S.P gm2.5 Saccharin sodium gm 12.5 Cyclamate sodium gm 2.5 Glycerin ml 3000Tragacanth powder gm 100 Orange oil flavor gm 10 F. D. and C. orange dyegm 7.5 Deionized water, q.s. tsp ml 10,000

One teaspoonfull (5 ml.) three times daily is employed in the treatmentof hypercholesteremia in adult humans.

Exam Ie 18.-A ue0us sus ensz'on 0r iiz'ection A suspending vehicle isprepared from the following materials:

Polyethylene glycol 4000 gm 30 Potassium chloride gm 11.2 Polysorbate gm2 Methylparaben gm 1.8 Propylparaben grn 0.2 Water for injection, q.s ml1000 The parabens are added to a major portion of the water and aredissolved therein by stirring and heating to 65 C. The resultingsolution is cooled to room temperature and the remainder of theingredients are added and dissolved. The balance of the water to make upthe required volume is then added and the solution sterilized byfiltration. The sterile vehicle thus prepared is then mixed with 50 gm.of 7a-methyl-l9-nor-3,5-androstadiene-3,17B-dihydroxy 3,17-acetate whichhas been previously reduced to a particle size less than about 10microns and sterilized with ethylene oxide gas. The mixture is passedthrough a sterilized colloid mill and filled under aseptic conditionsinto sterile containers which are then sealed.

Each milliliter of this suspension contains 59 mg. of 7 amethyl-19-nor-3,5 -androstadiene-3 ,17B-dihydroxy 3,17-diacetate. The suspension isused intramuscularly in 1-ml. doses in the treatment ofhypercholesteremia.

We claim:

1. 7a-methyl-3,5-androstadiene-3,17,B-diol tatc.

2. 7a,17a-dimethyl-3,S-androstadiene 3,17B-diol 3,17- diacetate.

3. 7a,17a-dimethyl-3,5-androstadiene-3,17p-diol 3-acetate.

4. 2a,7a-dimethyl-3,5-androstadiene-3,17,8-di0l 3,17-diacetate.

5. 3-ethoxy-7a-methyl-19-nor-3,5-androstadien-17-one.

6. 3ethoxy-2a,7a-dimethyl-3,5-andr0stadien-17-one.

7. 2a,7ot dimethyl 17 chlorethynyl 3,5 androstadiene-3,17B-diol3-acetate.

8. 7a-methyl-17a-ethyl-3,5-androstadiene-3,17,6-diol 3- acetate.

9. 2a,7a dimethyl 17oz n propyl 3,5 androstadiene-3,17fl-diol 3-acetate.

3,17-diace- 10. A process for the production of a compound of theformula l a R2" z '0- wherein R and R are selected from the groupconsisting of hydrogen and methyl; Z is the lower acyl radical of anorganic carboxylic acid containing from one to twelve carbon atoms,inclusive; M is selected from the group consisting of o o oz i -0509.)and o m) v CH3 we P. J R2" Wherein R R and M have the same meaning asabove, (2) followed by reaction with a compound selected from the groupconsisting of an anhydride and a chloride of an organic carboxylic acidcontaining from one to twelve carbon atoms, inclusive.

11. A method for reducing blood cholesterol in mammals comprising:administering to mammals a compound of the formula wherein R and R areselected from the group consisting of hydrogen and methyl; Z is selectedfrom the group consisting of lower alkyl of from one to twelve carbonatoms, inclusive, and the lower acyl radical of a hydrocarbon carboxylicacid containing from one to twelve carbon atoms, inclusive; M isselected from the group consisting of Wherein A is selected from thegroup consisting of hydrogen, lower alkyl of from one to twelve carbonatoms, inclusive, chlorine, bromine and trifiuoromethyl, R is selectedfrom the group consisting of hydrogen, lower alkyl of from one to twelvecarbon atoms, inclusive, and Z is selected from the group consisting ofhydrogen and the lower acyl radical of a hydrocarbon carboxylic acidcontaining from one to twelve carbon atoms, inclusive.

12. A compound of the formula and wherein R and R are selected from thegroup consisting of hydrogen and methyl; Z is seelcted from the groupconsisting of hydrogen and acetyl and Z is acetyl.

13. A compound of the formula wherein R and R are selected from thegroup consisting of hydrogen and methyl.

14. A compound of the formula wherein R is selected from the groupconsisting of ethyl and n-propyl and R is selected from the groupconsisting of hydrogen and methyl.

References Cited UNITED STATES PATENTS 1/1965 Cotton 260239.57

7/1965 Nakanishi 260-3973 OTHER REFERENCES Villotti et al.: If our.Amer. Chem. Soc., vol. 81 (1959)., p. 4566.

Nussbaum et al.: Journal Org. Chem, vol. 26 (1961),

Nes et al.: Tetrahedron (1963), vol. 19, pp. 299 to 307.

Steroid Drugs, v01. 11 (Applezweig), 1964, p. 119.

ELBERT L. ROBERTS, Primary Examiner.

